title: Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia.
abstract: Chimeric genes can be caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. We hypothesize that brain-expressed chimeras may contribute to schizophrenia. Individuals with schizophrenia and control individuals were screened genome wide for copy-number variants (CNVs) that disrupted two genes on the same DNA strand. Candidate events were filtered for predicted brain expression and for frequency < 0.001 in an independent series of 20,000 controls. Four of 124 affected individuals and zero of 290 control individuals harbored such events (p = 0.002); a 47 kb duplication disrupted MATK and ZFR2, a 58 kb duplication disrupted PLEKHD1 and SLC39A9, a 121 kb duplication disrupted DNAJA2 and NETO2, and a 150 kb deletion disrupted MAP3K3 and DDX42. Each fusion produced a stable protein when exogenously expressed in cultured cells. We examined whether these chimeras differed from their parent genes in localization, regulation, or function. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 differed from their parent genes. On the basis of the expression profile of the MATK promoter, MATK-ZFR2 is likely to be far more highly expressed in the brain during development than the ZFR2 parent gene. MATK-ZFR2 includes a ZFR2-derived isoform that we demonstrate localizes preferentially to neuronal dendritic branch sites. These results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization.
authors.affiliation: Departments of Medicine and of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: cfields@uw.edu.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Rippey
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.forename: Matt
authors.initials: M
authors.lastname: Brodsky
authors.forename: Alex S
authors.initials: AS
authors.lastname: Nord
authors.forename: Molly
authors.initials: M
authors.lastname: Gasperini
authors.forename: Sarah
authors.initials: S
authors.lastname: Pierce
authors.forename: Cailyn
authors.initials: C
authors.lastname: Spurrell
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.forename: Jon M
authors.initials: JM
authors.lastname: McClellan
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D020131:Genes, Duplicate; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D057809:HEK293 Cells; D006801:Humans; D050506:Mutant Chimeric Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
chemical_list: D050506:Mutant Chimeric Proteins; D012333:RNA, Messenger